RESUMO
BACKGROUND: Treatment of multidrug-resistant (MDR) tuberculosis with linezolid is characterized by high rates of adverse events. Evidence on therapeutic drug monitoring to predict drug toxicity is scarce. This study aimed to evaluate the association of linezolid trough concentrations with severe toxicity. METHODS: We retrospectively assessed consecutive patients started on linezolid for MDR tuberculosis between 2011 and 2017. The primary outcome was severe mitochondrial toxicity (SMT) due to linezolid, defined as neurotoxicity or myelotoxicity leading to drug discontinuation. The impact of plasma linezolid trough concentrations >2 mg/L was assessed in multivariate Cox proportional hazards models including time-varying covariates. RESULTS: SMT occurred in 57 of 146 included patients (39%) at an incidence rate of 0.38 per person-year (95% confidence interval, .30-.49). A maximum linezolid trough concentration >2 mg/L was detected in 52 patients (35.6%), while the mean trough concentration was >2 mg/L in 22 (15%). The adjusted hazard ratio for SMT was 2.35 (95% confidence interval, 1.26-4.38; P = .01) in patients with a mean trough concentration >2 mg/L and 2.63 (1.55-4.47; P < .01) for SMT after the first detection of a trough concentration >2 mg/L. In an exploratory analysis, higher maximum trough concentrations were dose-dependently associated with toxicity, while lowering elevated trough concentrations did not restore baseline risk. CONCLUSIONS: Linezolid trough concentrations >2 mg/L are strongly associated with the development of severe treatment-emergent toxicity in patients treated for MDR tuberculosis. Pending further prospective evidence, an individual risk-benefit assessment on the continuation of linezolid treatment is warranted in any patient with trough concentrations >2 mg/L.
Assuntos
Antituberculosos , Tuberculose Resistente a Múltiplos Medicamentos , Humanos , Linezolida/efeitos adversos , Antituberculosos/efeitos adversos , Estudos Retrospectivos , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Monitoramento de MedicamentosRESUMO
Background: Intermittent treatment could improve the convenience, tolerability and cost of ART, as well as patients' quality of life. We conducted a 48 week multicentre study of a 4-days-a-week antiretroviral regimen in adults with controlled HIV-1-RNA plasma viral load (VL). Methods: Eligible patients were adults with VL <â50 copies/mL for at least 1 year on triple therapy with a ritonavir-boosted PI (PI/r) or an NNRTI. The study protocol consisted of the same regimen taken on four consecutive days per week followed by a 3 day drug interruption. The primary outcome was the proportion of participants remaining in the strategy with VL <â50 copies/mL up to week 48. The study was designed to show an observed success rate of >â90%, with a power of 87% and a 5% type 1 error. The study was registered with ClinicalTrials.gov (NCT02157311) and EudraCT (2014-000146-29). Results: One hundred patients (82 men), median age 47 years (IQR 40-53), were included. They had been receiving ART for a median of 5.1 (IQR 2.9-9.3) years and had a median CD4 cell count of 665 (IQR 543-829) cells/mm3. The ongoing regimen included PI/r in 29 cases and NNRTI in 71 cases. At 48 weeks, 96% of participants (95% CI 90%-98%) had no failure while remaining on the 4-days-a-week regimen. Virological failure occurred in three participants, who all resumed daily treatment and became resuppressed. One participant stopped the strategy. No severe treatment-related events occurred. Conclusions: Antiretroviral maintenance therapy 4 days a week was effective for 48 weeks in 96% of patients, leading to potential reduction of long-term toxicities, high adherence to the antiretroviral regimen and drug cost saving.
Assuntos
Antirretrovirais/administração & dosagem , Infecções por HIV/tratamento farmacológico , HIV-1/efeitos dos fármacos , Inibidores da Transcriptase Reversa/administração & dosagem , Adulto , Antirretrovirais/uso terapêutico , Contagem de Linfócito CD4 , Esquema de Medicação , Quimioterapia Combinada , Feminino , Infecções por HIV/virologia , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Qualidade de Vida , RNA Viral/sangue , Inibidores da Transcriptase Reversa/uso terapêutico , Resultado do Tratamento , Carga Viral/efeitos dos fármacosRESUMO
Bedaquiline, a recently approved drug for the treatment of multidrug-resistant tuberculosis (MDR-TB), is recommended for a duration of 24â weeks. There are scarce data on patients treated with this drug outside clinical trials.All MDR-TB patients who started treatment from January 1, 2011 to December 31, 2013 and received ≥30â days of bedaquiline were included in a multicentre observational cohort.Among 45 MDR-TB patients, 53% harboured isolates resistant to both fluoroquinolones and second-line injectables, and 38% harboured isolates resistant to one of these drug classes. Median bedaquiline treatment duration was 361â days and 33 patients (73%) received prolonged (>190â days) bedaquiline treatment. Overall, 36 patients (80%) had favourable outcome, five were lost to follow-up, three died, and one failed and acquired bedaquiline resistance. No cases of recurrence were reported. Severe and serious adverse events were recorded in 60% and 18% of patients, respectively. Values of Fridericia-corrected QT interval (QTcF) >500â ms were recorded in 11% of patients, but neither arrhythmias nor symptomatic cardiac side-effects occurred. Bedaquiline was discontinued in three patients following QTcF prolongation. No significant differences in outcomes or adverse events rates were observed between patients receiving standard and prolonged bedaquiline treatment.Bedaquiline-containing regimens achieved favourable outcomes in a large proportion of patients. Prolonged bedaquiline treatment was overall well tolerated in this cohort.
Assuntos
Antituberculosos/administração & dosagem , Diarilquinolinas/administração & dosagem , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Adulto , Antituberculosos/efeitos adversos , Diarilquinolinas/efeitos adversos , Feminino , França , Humanos , Estimativa de Kaplan-Meier , Modelos Logísticos , Masculino , Análise Multivariada , Mycobacterium tuberculosis , Estudos Retrospectivos , Escarro/microbiologia , Resultado do TratamentoRESUMO
We report 20 cases of extensively drug-resistant tuberculosis managed in France. Treatment was individualized and included bedaquiline and linezolid for most patients and surgery in 8 patients. At last follow-up (22 months), 19 patients had achieved conversion from positive to negative on culture testing. These promising results of comprehensive management obtained in a small series deserve confirmation.
Assuntos
Tuberculose Extensivamente Resistente a Medicamentos/epidemiologia , Tuberculose Extensivamente Resistente a Medicamentos/terapia , Mycobacterium tuberculosis , Adulto , Antituberculosos/farmacologia , Antituberculosos/uso terapêutico , Terapia Combinada , Tuberculose Extensivamente Resistente a Medicamentos/história , Feminino , Seguimentos , França/epidemiologia , História do Século XXI , Humanos , Masculino , Mycobacterium tuberculosis/efeitos dos fármacos , Resultado do TratamentoRESUMO
BACKGROUND: Bedaquiline is a new antibiotic that was approved for the treatment of multidrug-resistant (MDR) tuberculosis. We aimed to evaluate the short-term microbiological efficacy and the tolerability profile of bedaquiline. METHODS: We performed a retrospective cohort study among patients with MDR tuberculosis receiving bedaquiline for compassionate use between January 2010 and July 2013 and evaluated at 6 months of bedaquiline treatment. RESULTS: A total of 35 patients with MDR tuberculosis were included in the study. Nineteen (54%) had extensively drug-resistant (XDR) tuberculosis, and 14 (40%) had isolates resistant to fluoroquinolones (Fqs) or second-line injectables. Bedaquiline was associated with a median of 4 (range, 2-5) other drugs, including linezolid in 33 (94%) cases. At 6 months of bedaquiline treatment, culture conversion was achieved in 28 of 29 (97%) cases with culture-positive pulmonary tuberculosis at bedaquiline initiation. Median time to culture conversion was 85 days (range, 8-235 days). Variables independently associated with culture conversion were treatment with a Fq (P = .01), absence of lung cavities (P < .001), and absence of hepatitis C virus infection (P = .001). A total of 7 patients (20%) experienced a ≥60-ms increase in QT interval, leading to bedaquiline discontinuation in 2 (6%) cases. Severe liver enzyme elevation occurred in 2 patients (6%). During the study period, 1 death (3%) occurred and was reported as unrelated to tuberculosis or antituberculosis treatment. CONCLUSIONS: The use of bedaquiline combined with other active drugs has the potential to achieve high culture conversion rates in complicated MDR and XDR tuberculosis cases, with a reassuring safety profile at 6 months of treatment.
Assuntos
Antituberculosos/uso terapêutico , Ensaios de Uso Compassivo , Diarilquinolinas/uso terapêutico , Tuberculose Extensivamente Resistente a Medicamentos/tratamento farmacológico , Adolescente , Adulto , Idoso , Antituberculosos/efeitos adversos , Estudos de Coortes , Diarilquinolinas/efeitos adversos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Feminino , França , Humanos , Masculino , Pessoa de Meia-Idade , Mycobacterium tuberculosis/isolamento & purificação , Estudos Retrospectivos , Resultado do Tratamento , Adulto JovemAssuntos
Infecções por Coronavirus/complicações , Pneumonia Viral/complicações , Tuberculose Pulmonar/complicações , Adulto , Idoso , Antituberculosos/uso terapêutico , Antivirais/uso terapêutico , Azitromicina/uso terapêutico , Betacoronavirus , COVID-19 , Teste para COVID-19 , Técnicas de Laboratório Clínico , Estudos de Coortes , Coinfecção , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/tratamento farmacológico , Combinação de Medicamentos , Emigrantes e Imigrantes , Feminino , Humanos , Hidroxicloroquina/uso terapêutico , Lopinavir/uso terapêutico , Pulmão/diagnóstico por imagem , Masculino , Pessoa de Meia-Idade , Mortalidade , Pandemias , Pneumonia Viral/diagnóstico , Pneumonia Viral/tratamento farmacológico , Ritonavir/uso terapêutico , SARS-CoV-2 , Tomografia Computadorizada por Raios X , Tuberculose/complicações , Tuberculose/diagnóstico , Tuberculose/tratamento farmacológico , Tuberculose Pulmonar/diagnóstico , Tuberculose Pulmonar/tratamento farmacológico , Tratamento Farmacológico da COVID-19Assuntos
Antituberculosos/administração & dosagem , Diarilquinolinas/administração & dosagem , Nitroimidazóis/administração & dosagem , Oxazóis/administração & dosagem , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Adulto , Antituberculosos/efeitos adversos , Ensaios Clínicos como Assunto , Diarilquinolinas/efeitos adversos , Esquema de Medicação , França , Humanos , Letônia , Masculino , Nitroimidazóis/efeitos adversos , Oxazóis/efeitos adversos , Segurança do Paciente , Resultado do TratamentoRESUMO
We report Campylobacter fetus meningitis associated with endocarditis in a 75-year-old diabetic man after he consumed raw liver. C. fetus was isolated from blood samples and cerebrospinal fluid. Cure was obtained with combined intravenous imipenem-gentamicin for 4 weeks; no relapse occurred after 6 months of follow-up.